The present disclosure provides methods to produce non-human animal models for diseases that have a poor life-expectancy. The animal models provided herein are the result of gene editing to result in genetic lesions that recapitulate human diseases by virtue of introgressing lethal, dominant negative or non-functional mutations in animal genomes corresponding to those responsible for human diseases. In some cases, the genomic edit may result in a low number of pregnancies carried to term and/or a failure to thrive phenotype with those born failing to survive to sexual maturity. The present disclosure provides methods to produce non-chimeric animals containing a detrimental genetic lesion from healthy chimeric animals. In this method, the chimeric animals are derived from cells in which the genetic lesion is made with the defect being complemented by the genome of an animal that is gametogenically deficient (cannot produce gametes) and cannot pass on its own genes. Thus, the gametes of the chimera are completely derived from the edited animal. When a male and female chimera are mated with each other, the offspring are 100% of the edited genome.

Methods for neutralizing and/or removing human GM-CSF in a subject in need thereof, comprising administering to the subject CAR-T cells having a GM-CSF gene knockout (GM-CSF.sup.k/o CAR-T cells) are provided. Also provided are methods for GM-CSF gene inactivation or GM-CSF knockout (KO) in a cell comprising targeted genome editing or GM-CSF gene silencing. Methods for preventing/treating immunotherapy-related toxicity, comprising administering to the subject CAR-T cells having a GM-CSF gene inactivation or GM-CSF knockout (GM-CSF.sup.k/o CAR-T cells), wherein the GM-CSF gene is inactivated or knocked out and/or or a recombinant GM-CSF antagonist are provided. Methods for reducing a level of a cytokine or chemokine other than GM-CSF in a subject having immunotherapy-related toxicity comprising administering to the subject a recombinant hGM-CSF antagonist are provided. Also provided are methods for treating or preventing immunotherapy-related toxicity in a subject, comprising administering to the subject chimeric antigen receptor-expressing T-cells (CAR-T cells), the CAR-T cells having a GM-CSF gene knockout (GM-CSF.sup.k/o CAR-T cells). Methods for preventing or reducing blood-brain barrier disruption in a subject treated with immunotherapy, the method comprising administering CAR-T cells having a GM-CSF gene knockout (GM-CSF.sup.k/o CAR-T cells) to the subject, also are provided.

This invention relates to a transgenic non-human mammal whose genome comprises a polynucleotide sequence encoding a T cell receptor that is specific to a fluorescent protein, where the T cell of the non-human mammal comprises the T cell receptor. The present invention also relates to an isolated T cell from the transgenic non-human mammal of the present invention, an isolated T cell comprising an expression construct comprising a polynucleotide sequence that encodes a T cell receptor that is specific to a fluorescent protein, methods of making transgenic non-human mammals comprising T cell receptors that are specific to a fluorescent protein, a method of depleting cells in a non-human mammal using isolated T cells that encode a T cell receptor that is specific to a target protein, and a method of characterizing a T cell response to an agent.

An object of the present invention is to provide an immunodeficient mouse which is capable of eliminating effects of immune cells from the immunodeficient mouse against human antibodies and in which human cells are engrafted at high level.

Deletion of a mouse FcgR gene from an NOG mouse results in a mouse that does not exhibit antibody-dependent cellular cytotoxic activity on tumors, and in the mouse, human cells can be engrafted at significantly higher level than that in the NOG mouse. Furthermore, by introducing the human IL-15 gene into the mouse and engrafting a human NK cell in the mouse, only human NK cells become effector cells to enable evaluation of ADCC activity.

Genetically modified non-human animals and methods and compositions for making and using them are provided, wherein the genetic modification comprises a deletion of the endogenous low affinity FcγR locus, and wherein the mouse is capable of expressing a functional FcRγ-chain. Genetically modified mice are described, including mice that express low affinity human FcγR genes from the endogenous FcγR locus, and wherein the mice comprise a functional FcRγ-chain. Genetically modified mice that express up to five low affinity human FcγR genes on accessory cells of the host immune system are provided.

The present invention relates to a fusion proteins comprising regulatory T cell protein, VISTA (V-domain Immunoglobulin Suppressor of T cell Activation (PD-L3) and an immunoglobulin protein (Ig), preferably also containing a flexible linker intervening the VISTA and Ig Fc polypeptide. The invention also provides the use of VISTA polypeptides, multimeric VISTA polypeptides, VISTA-conjugates (e.g., VISTA-Ig), and VISTA antagonists for the treatment of autoimmune disease, allergy, and inflammatory conditions, especially lupus, multiple sclerosis, psoriasis, psoriatic arthritis, multiple sclerosis, Crohn's disease, inflammatory bowel disease and type 1 or type 2 diabetes.

Non-human animals, cells, methods and compositions for making and using the same are provided, wherein the non-human animals and cells comprise a humanized B-cell activating factor gene. Non-human animals and cells that express a human or humanized B-cell activating factor protein from an endogenous B-cell activating factor locus are described.

Non-human animals, cells, methods and compositions for making and using the same are provided, wherein the non-human animals and cells comprise a humanized a proliferation-inducing ligand gene. Non-human animals and cells that express a human or humanized a proliferation-inducing ligand protein from an endogenous a proliferation-inducing ligand locus are described.

To identify a microorganism causing the development of primary sclerosing cholangitis associated with ulcerative colitis. A Klebsiella pneumoniae strain inducing inflammation in the liver.

To identify a microorganism causing the development of primary sclerosing cholangitis associated with ulcerative colitis. A Klebsiella pneumoniae strain inducing inflammation in the liver.